The inactivation of the prototype NF-kB inhibitor, IkBa, occurs through a series of ordered processes including phosphorylation, ubiquitin conjugation and proteasome-mediated degradation (Ub-Pr). We previously detected a 97 kDa protein co-immunoprecipitated with IkBa, and identified it as the valosin-containing protein (VCP), a member of the AAA ATPases a ssociated with a variety of cellular activities) family. Biochemical studies demonstrated that phosphorylation and ubiquitination of IkBa are required for its binding to VCP, which subsequently is required for the degradation of IkBa. Furthermore, VCP copurified with the 26S proteasome in highly purified proteasome preparations. We recently generated a panel of antisera against VCP and found that VCP preferentially associated with the uniquitinated forms of IkBa, and VCP co-immunoprecipitated with other subunits of the proteasome. These results strongly suggest that VCP provides a functional and physical link between the IkBa and the proteasome in Ub-Pr mediated degradation pathway. We propose a model for IkBa inactivation in which ubiquitinated IkBa conjugates become physically associated with VCP which displaces the NF-kB dimer, thus releasing the dimer for translocation into the nucleus. The ubiquitinated IkBa is then chaperoned to the 26S proteasome for degradation. Currently, we are searching for other Ub-Pr substrates that are also chaperoned by VCP, and several proteins have been identified.